FR2551057A1 - NOVEL AGLYCONES USEFUL FOR ANTIBIOTIC AND ANTITUMOR PREPARATION OF THE ANTHRACYCLIN SERIES AND METHODS FOR THEIR PREPARATION - Google Patents

Abstract

THE PRESENT INVENTION RELATES TO NEW AGLYCONES WHICH MEET THE GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH: R, R, R, R WHICH MAY BE IDENTICAL OR DIFFERENT REPRESENT A HYDROGEN ATOM OR A OH, OMETAL GROUP , OR; R BEING A SUBSTITUTE ALKYL GROUP OR NOT IN CAC; R REPRESENTS A HYDROGEN ATOM OR A COCHR GROUP, R IS HYDROGEN OR AN ALKYL, HYDROXYL, ALCOXYL OR ARYL GROUP; R AND R, WHICH ARE ALWAYS DIFFERENT, REPRESENT EITHER A HYDROGEN ATOM OR AN OH GROUP; R REPRESENTS A HYDROGEN ATOM OR THE CHCO- GROUP. APPLICATION FOR THE PREPARATION OF ANTIBIOTICS AND ANTITUMORS.

Description

The present invention relates to new useful aglycones

  for the preparation of anthracycline antibiotics and antitumour drugs and their

processes of preparation.

  Anthracyclines represented by the following general formula (I): o

1 12 11 10 13

2 4 5 (I)

  o O, 4 constitute an important family of antibiotics and antitumorals Some members of this family (such as daunorubicin and doxorubicin) are used clinically successfully for the treatment of various

  forms of cancer (acute leukemias, breast cancers, urinary tract cancers, HODGKIN disease, etc.).

  Their remarkable cytotoxic activity is nevertheless

  limited by adverse side effects, and in particular by a significant cardiotoxicity This one related to the dose of antibiotic used requires the irreversible interruption of treatment from a certain threshold.

  Many efforts have been made in recent years to improve the therapeutic index.

  of these compounds: a decrease in cardiotoxicity appears to be more important than an increase in their weight effectiveness.

  The modifications made concern aglycone and / or sugar by total synthesis or by biosynthesis

or by semisynthesis.

  The modifications carried out relate to all cycles (ABCD) as well as to sugar. The products obtained are generally classified in various categories according to the substitution of cycle B: I Dihydroxy derivatives in 6 and in 11 (in this category belong daunorubicin compound II and the

doxorubicin compound III).

O OH O

COMPOUND (II) = R = H Me O OH

COMPOUND III) = R = OH

  HO O NH 2 DAUNORUBICIN II): Simultaneous discovery in Italy

  (Farmitalia) and France (Rhone-Poulenc) DOXORUBICIN (II): Isolated from Streptomyces peucetius var. 20 caesius in 1969 (Farmitalia).

  II Monohydroxy derivatives in 6 (Deoxy-11 series) III Monohydroxy derivatives in 11 (Deoxy-6 series)

  I EXAMPLES OF DIHYDROXYL DERIVATIVES IN 6 AND 11

  1 D-ring modification tests The demethoxylated analogs in position 4 of the compounds (II) and (III) have been prepared and have a therapeutic index superior to the natural compounds, (F ARCAMONE,

  Anticancer Antibiotics, Academic Press, 1981, chapter 7).

  In addition, various substituents have been introduced: in position 1 and 4 (Cl, CH 3), or 2 and 3 (Cl, CH 3 or benzo) (Cf.

  F ARCAMONE and A 1 Experientia 34, 1255, 1978).

  The benzene ring D has been replaced by an aromatic sulfur heterocycle (A S KENDE, B NEWMAN, Eur Pat Appli

17469, October 15, 1980).

  2 Cycle modification tests Relatively little carried out However, it is necessary to mention the preparation of imino-5-daunorubicin (L TONG,

  D.W. HENRY and E. ACTON, J. Med Chem, 22, 36 (1979)).

  3 Cycle A Modification Assays Many analogues have been prepared most often by semisynthesis by transformation of natural products: derivatives with OCH 3 at 10 or 8, 9-deoxy (with or without a double bond A-9) chain compounds modified side

  (9-deaacyl), reduced products, carbonyl derivatives in position 13 (see F ARCAMONE, Anticancer Antibiotics, already cited).

  4 Sugar Modification Tests Changes have been made to all

  (1 ', 2', 3 ', 4', 5 ', 6') positions of the pyranucleic ring, antitumor activity "in vivo" has often been preserved or improved.

  EXAMPLE 6 MONOHYDROXYLS (1-Deoxy series) The deoxy-dauno and doxorubicin derivatives were obtained by fermentation in 1980 with Famitalia They exhibit "in vivo" antitumour activity similar to that of the compounds (I) and III) at higher doses but with a

less toxicity.

  Numerous total syntheses of the corresponding aglycones have been described (see, in particular, GESSON and MONDON, Chem Comm., 1982, 421), in addition to that of 4-demethoxy-1-deoxyunorubicin and doxorubicin.

  (UMEZAWA et al., J. Of Antibiotics 33, 1581 (1980).

  It is also necessary to point out the existence of natural compounds of the family of anthracyclines having no hydroxyl at position 11: aclacinomycins, pyrromycines, cerubines, etc. III EXAMPLE OF DERIVATIVES EN 11 (6-Deoxy series)

  Some naturally occurring anthracyclines lacking hydroxyl at the 6-position: α-citromycin, c 2 -rhodo-mycine are known.

  On the other hand, 6-deoxy-dauno or doxorubicin do not

  not yet isolated or synthesized.

  In a recent publication F ARCAMONE et al.

  (J Org Chem, 48, 405, 1983) describe the synthesis of 4-demethoxy deoxy 6 daunorubicin whose first in vitro tests (HeLa cells) show cytotoxicity

  similar to that of daunorubicin.

  The mode of action of all these molecules is probably complex. It is admitted that it involves intercalation in the DNA chain, a favorable process because of

  partial flatness of the tetracyclic system.

  The molecule then undergoes a reduction leading, in the first instance, to a radical ion which would be at the origin of the formation of toxicities (ex: HO ', H 202) at the level of the tissues, then of that of a reduced form of the quinone system This form would be responsible for the elimination of sugar and free aglycone formation

  (without oxygen function in position 7).

  These considerations led HANSCH et al. (Il Farmaco 35, 12, 965 (1980)) to suggest the introduction of

  small donor groups (OH, OCH 3) in position 2 or 3.

  It can indeed be thought that the introduction of various substituents into the D ring, by modifying the oxidation-reduction potential of the quinone system, could limit these various reactions and lead to compounds with a higher therapeutic index. This implies the synthesis of new compounds by many researchers, and the search for a possible correlation between the potential for oxidation-reduction

  and / or antitumor activity and / or toxicity.

  The Applicant by studying and examining all these results obtained by the various researchers on the one hand, while also noting that: I in series deoxy-11, all other things being equal, certain natural compounds having a hydroxyl in position 35 1 have a stronger antitumor activity than the non-hydroxylated compounds at the same position (eg relative activities of cinerubin A and aclacinomycin A) (Ref. ST CROOK and S D. REICH, Anthracyclines, Academic Pres 1980, Chapter

6).

  The reductive elimination process of L-daunosamine is certainly accelerated by the presence of phenol in the peril position and this by analogy with the rapid and selective hydrogenolysis of a benzyl alcohol function at position 10 in α-citromycinone.

O OH OH O OH

H 2 Pd / Ba 504

OH H O OH

  a citromycinone and citromycinone was able to synthesize a whole series of aglycone compounds

  likely to provide very active and slightly toxic drugs.

  The present invention relates to novel aglycones useful for the preparation of antibiotics and antitumour agents characterized in that they correspond to the following general formula IV: R 1 O R 7

R 2 OR 8

R 3

R 5 O R 6 OH

  in which: R 1, R 2, R 3 and R 5, which may be identical or different, represent a hydrogen atom or an OH, O metal, OR 4 group,

  R 4 is a substituted or unsubstituted alkyl group of 1 to 6 carbon atoms.

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  R represents a hydrogen atom or a COCH 2 group R ', R' being

  hydrogen, alkyl, hydroxyl, alkaxyl or aryl.

  R 6 and R 7, which are always different, represent either an atom

hydrogen is an OH group.

  R 8 represents a hydrogen atom or the CH 3 CO group reserves that: 1 R 1, R 2 and R 3 are never hydrogen at a time when R 7 and

  R 8 represents the hydrogen atom and R is the COCH 2 R 'group.

  If R 1, R 2, R 3, and R 6 are hydrogen, R 5 is different from hydrogen and OCH 3.

  According to the invention, the two OH groups of the ring A are in the cis or trans position with respect to each other.

  According to an advantageous embodiment of the subject of the invention,

  the products obtained are aglycones désocy-11.

  According to another advantageous embodiment of the subject of the invention,

  the products obtained are 6-diketoaglycones.

  According to the invention, the dioxyn-11 aglycones are taken from the group which comprises: the aglycone wherein R 1 = OH; R 2 = R 3 = R 5 = H; R 6 = OH; R = COCH 3; R 8 = H 20 the aglycine wherein R 1 R = 3 R 5 = H; R 2 = OCH 3; R 6 = OH; R = COXH 3; R 8 = H the aglycone in which R 1 = R 2 = R 5 = H; R 3 = OCH 3, R 6 = CH; R = COCH 3; R 8 = H the aglycone in which R 1 = R 2 = R 3 = = R = H; R 6 = CH; R 8 = COCH 3 According to an advantageous embodiment of the subject of the invention, the 6-deoxy aglycone corresponds to the product in which:

  R 1 = R 2 = R 3 = R 6 = H; R 7 = OH; R 5 = OH; R = COCH 3

  The present invention also relates to a process for preparing the deoxy-11 aglycones according to the present invention, which process is characterized by the following steps: Step 7: R 2 Preparation of the enol ether of general formula V

R 1 O

  O-Alkyl (V) R 3 R 1, R 2, R 3 and R 5 having the same meaning as above

  by action of a halogenated naphthoquinone of general formula VI on a diene of general formula VII.

R 1 O

  O-Alkyl R 5 I Alkyl O Si Alkyl Alkyl (VI) (VII) R 1, R 2, R 3 and. 2nd step R 5 having the same meaning as above

  and X represents a halogen atom. Hydrolysis of enol ether V to the corresponding ketone of general formula VIII

R 1 O

R 20

R 5 O OH

R (VITI)

  Ethyl nylation of ketone VIII to the corresponding product of formula IX.

3rd stage Rî O

C CH 'OH

(IX)

R 5 O OH

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  followed by hydration in the product of general formula X

R 1 O

(X)

R 2 I H

R 3

R 5 O OH

  4th step: Bromination-benzyl alcohol use of hydroquinase 10 leading to the desired product.

  The present invention furthermore relates to a process for the preparation of 6-deoxy aglycones according to the present invention, which process is characterized in that during the first step a diene of the general formula XI O-Alkyl is used. O Alkyl Alkyl Alkyl Si-o (XI) Alkyl / 3 XI The other steps being similar to the process described for

the deoxy-11 derivatives.

  In addition to the foregoing, the invention also includes other provisions which will emerge from the

  following description which refers to examples of

  preparation of products according to the present invention.

  It should be understood, however, that these examples are for illustrative purposes only

  of the invention and have no limiting character.

9 -

  EXAMPLE 1 PREPARATION OF 5-HYDROXY METHOXY-8 DIHYDRO-3,4

1H-NAPHTACENETRIONE-2,6,11,

  To a solution of 3-chloro-6-methoxy-1,2-naphthoquinone (1.9 g, 8.6 mmol) in tetrahydrofuran (THF) (20 ml) was added dropwise OC ketene acetal VII (2.5 g, 8.9 mmol) in solution in THF (3 ml)

  The reaction medium is stirred overnight at room temperature.

  After evaporation of the solvent, the solid obtained is slowly added to a solution of HF (25 ml) -Sb F (5 ml) at 40 ° C. in a teflon flask. The mixture is kept at -40 ° C. for 20 minutes and then poured slowly on 500 ml of ice-water mixture After extraction with methylene chloride, the organic phase is washed with water, dried over sodium sulfate and then evaporated. The tetracyclic ketone is purified by pressure chromatography (eluent: CH 2 C 12)

(1.11 g, 40%).

  EXAMPLE 2 PREPARATION OF () DIHYDROXY-2,5-ETHYNYL-2-METHOXY-8-TETRAHYDRO-1,2,3,4-NAPHTHACENEDIONE6,11

  Purified acetylene is bubbled for 1 hour by a first pass through a trap cooled with ice and then by a trap containing concentrated sulfuric acid, through 40 ml of anhydrous THF. Ethylmagnesium bromide (40 ml 1 M in THF, 40 mmol) is then added dropwise After addition, the solution is evaporated under reduced pressure, taken up in 80 ml of methylene chloride (CH 2 Cl 2) distilled over P 205 to this cooled solution. at 40 ° C., the ketone prepared in Example 1 (386 mg, 1.2 mmol) dissolved in CH 2 Cl 2 (150 ml) is added dropwise. The reaction mixture is stirred for 1 hour between 40.degree. Before being hydrolysed with a 0.1 N hydrochloric acid solution and then conventionally extracted with methylene chloride. Pressure chromatography (CH 2 C 12) 35 makes it possible to separate the starting ketone which has not reacted -

  (148 mg, 38%) of the ethynylcarbinol formed (165 mg, 43%).

  EXAMPLE 3 PREPARATION OF () DEMETHOXY-4 DIDESOXY-7,11

METHOXY-3 DAUNOMYCINONE

  The treatment of Amberlite resin IRN-77 with mercuric oxide Hg O is carried out in the following manner: the resin (50 g) is suspended in a solution of diluted H 2504 and then washed several times with water by decantation A solution of mercuric oxide (0.5 g) in 1 liter of dilute sulfuric acid is then added to the resin. The resin is again washed with water and then dried under

reduced pressure.

  A mixture of ethynylcarbinol, prepared as described in Example 2) (140 mg, 0.4 mmol) and H 2 O-treated resin (2 g) in 200 ml of ethanol and 40 ml of water is added. at reflux for 16 hours The cooled reaction mixture

  The filtrate is filtered off with methylene chloride.

  The organic phase is washed with water and dried over sodium sulfate Evaporation of the methylene chloride under reduced pressure leads to hydroxyketone (145 mg, 98%) which is used without further purification.

  EXAMPLE 4 PREPARATION OF () DEMETHOXY-4 DESOXY-11

METHOXY-3 DAUNOMYCINONE

  A solution, under nitrogen, of hydroxyketone X (I Omg, 0.27 mmol) of epoxyclohexane (132 mg, 1.35 mmol) in 250 ml of CC 14 and 50 ml of CH 2 C 12 is irradiated with 60 W lamp while a solution of bromine in CC 14 (0.36 ml of a 0.1 M solution diluted in ml of CC 14) is added dropwise. After addition, the solution is allowed to stir. The reaction medium is taken up in 60 ml of acetone. A solution of calcium hydroxide obtained from calcium oxide (48 mg of Ca 2 O, 0.82 mmol in 50 ml of water). The violet reaction mixture is left under stirring for 30 minutes before being neutralized with a saturated oxalic acid solution and extracted in a conventional manner with 1-methylene chloride. Chromatography under pressure (CH 2) C 12 -Me OH 99-1) makes it possible to separate the 4-methoxy-4-methoxy-4-methoxy-5-deethoxycinone (37.2 mg, 36%) from () epi-7-4-methoxy-1-deoxy-1-methoxy-daunomycinone (43.8 mg;

42.5%).

  EXAMPLE 5 PREPARATION OF () (ETHYLENEDIOXY-1,1 ETHYL)

  2-TRIHYDROXY-2,7,12 TETRAHYDRO-1,2,3,4 NAPHTACENEDIONE-6,11 A solution of () 2-acetyl-2,7,6-trihydroxy-1,2,3,4-tetrahydro-naphtacenedione -6.11 (740 mg, 2.1 mmol) and ethylene glycol (280 mg, 4.4 nmol) in the presence of a catalytic amount of paratoluene sulfonic acid in 400 ml of benzene is refluxed 12 hours in a 500-ml flask The flask is equipped with a "Dean Stark" (to remove water formed as an azeotrope

with benzene).

  After being washed with water, dried with sodium sulphate, the organic phase is evaporated to give the

dioxolane (816 mg, 98%).

  EXAMPLE 6 PREPARATION OF () DEMETHO XY-4 DESOXY-6 HYDROXY-4 DAUNOMYCINONE To a solution of dioxolane obtained as described in Example 5 (260 mg, 0.66 mmol), epoxycyclohexane (324 mg; 3 mmol) of isobutyronitrile azobis (30 mg, 0.18 mmol) in 400 ml of CC 14 is added at 45 ° C.

  bromine solution (8 ml of a 0.1 M solution, 0.8 mmol).

  The solution is maintained at this temperature for 3 hours and then concentrated under reduced pressure. The reaction medium is taken up in a solution of THF and 0.5 N sodium hydroxide solution.

  (1 to 1) and allowed to stir overnight at room temperature.

  After neutralization with 0.1 N HCl and conventional methylene chloride extraction, the crude reaction product is taken up in a solution of CF 3 COOH (20 ml) -H (4 ml) cooled to 0 ° C. and allowed to stir for 4 hours at room temperature. this temperature The solution is thrown on 200 ml of an ice-water mixture and

  extracted with methylene chloride.

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Aglycone (66 mg, 28%) obtained

O O OH O

I OH

  is purified by thin layer chromatography (CH 2 C 12 -Me OH; 98-2) EXAMPLE 7 PREPARATION OF () DEMETHOXY-4 DESACETYL-9 DIDESOXY-7,11 DAUNOMYCINONE To a solution of tetracyclic ketone VIII (3 g 10.2 mmol) in 900 ml of THF and 90 ml of water are slowly added cyanoborohydrurec sodium (6.2 g, 102 mmol). The solution is left stirring for a further 30 minutes and then extracted with methylene chloride. The organic phase, washed with water and dried over sodium sulphate, is evaporated under reduced pressure. to lead to the corresponding alcohol (2.95 g;

  98%) which does not require further purification.

  EXAMPLE 8 PREPARATION OF () O-ACETYL-9 DEMETHOXY-4

  DESACETYL-9 DIDESOXY-7,11 DAUNOMYCINONE

  A solution of the alcohol obtained as described in Example 7 (470 mg, 1.6 mmol) in 15 ml of acetic anhydride and 30 ml of pyridine is allowed to stir for 16 hours at -10 ° C. The organic phase is washed with a solution of 1N hydrochloric acid and then with water, dried over sodium sulfate. The solvent is dissolved in water-ice and extracted with methylene chloride.

  evaporated under reduced pressure Chromatography under pressure (eluent: CH 2 C 12) of the residue makes it possible to separate the acetate (430 mg, 80%) of the diacetate formed (54 mg, 9%) and the starting alcohol (24). mg, 5%).

13 2551057

  EXAMPLE 9 PREPARATION OF () O-ACETYL-9 DEMETHOXY-4 DESACETYL-9 DESOXY11 DAUNOMYCINONE

  A solution of the above compound (145 mg, 0.43 mmol) in 700 ml of CC 14, nitrogen under the presence of epoxycyclohexane (216 mg, 2.2 mmol) was irradiated with a 60 W lamp while A solution of bromine in CC 14 (4.8 ml of a 0.1 M solution diluted in ml of CC 14) is added dropwise. After addition, the solution is left stirring for 30 minutes and then concentrated under reduced pressure. The reaction medium is taken up in 100 ml of THF and 50 ml

  0.1 N hydrochloric acid, stirred at room temperature for 1 hour 30 minutes before being extracted with methylene chloride in a conventional manner.

  Chromatography under pressure (eluent: CH 2 C 12) of the crude product allows separation of 9-O-acetyl-9-demethoxy-4-desacetyl-9-deoxy-daunomycinone (43 mg, 28%) from the () cobalt. 7-acetyl-9-demethoxy-4-desacetyl-9

  deoxy-11 daunomycinone (74 mg, 49%).

CHARACTERISTICS

PRODUCTS OBTAINED

14 -

255 1,057

CH 3 (

  5-Hydroxy-9-methoxy-dihydro-314-1H-naphtacenetione-26-d 111

Yield: 40%.

M.P .: 232-234C.

  MS: m / z = 322 (96%), 294 (75%), 293 (67%), 280 (100%).

  IR (Pastille K Br): 2960 cm, 1710, 1670, 1630, 1590, 1570, 1490, 1470, 1430, 1420, 1370, 1345, 1310, 1295, 1280, 1230, 1170, 1110, 1085, 1060, 1030, 1000, 960, NMR (CD C 13): 2.6 ppm (triplet, J = 7 Hz, 2H); 3.27 (triplet, J = 7 Hz, 2H); 3.68 (singlet, 2H); 3.98 (singlet, 3H); 7, 23 (doublet of doublet, o J = 7 Hz and 2 Hz, 1 H); 7.53 (singlet, 1H); 7, 68 (doublet, J = 2 Hz, 1H); 8.20 (doublet, J = 7 Hz, 1H); 13.1 (singlet, 1H), CH 3

Q 'OH

O OH

  2-Dihydroxy-2-ethyl-2-methoxy-9-tetrahydro-1-3,4-naphtacenedione-6 11 Yield: 50% 2 O

Decomposition T 230 C.

  MS m / z = 348 (57%), 330 (70%), 322 (57%), 280 (100%).

  IR (Pastille K Br): 3530 cm -1, 3440 3290, 3240, 2960, 1670, 1630, 1600, IR (Pastille K Br): 3530 cm, 3440, 3290, 3240, 2960, 1670, 1630, 1600, 1470 , 1430, 1380, 1370, 1340, 1295, 1270, 1230, 1200, 1090,

  1020, 1010, 980, 940, 850, 820, 800, 750.

  NMR (CD C 13): 2.16 ppm (triplet, J = 7 Hz, 2H); 2.47 (singlet, 1H); 3.22 (singlet 2H); 3.03 (triplet, J = 7 Hz, 2H); 3.99 (singlet, 3H); 7.24 (doublet of doublet, J = 7 Hz, and 2 Hz, 1 H); 7.54 (singlet, 1H); 7.69

  (doublet, J = 2 Hz, 1H); 8.20 (doublet, J = 7 Hz, 1H); 13, 15 (singlet, 1H).

551,057

  ## STR2 ## 4-Methethoxy-1,2,3,4-tetrahydro-4-hexa-6-dione (4-methoxy) -5-methoxy-4-methoxy-2-methoxy-2-enoxane

P = 244-2460 ° C

  MS: m / z = 366 (10%), 348 (6%), 323 (100%), 305 (33%), 293 (25%), 280 (18%).

  -2 1.R (Pastille K Br): 3600 cm (fine), 2965, 1715, 1670, 1630, 1595, 1570, 1500, 1470, 1460, 1450, 1425, 1410, 1390, 1360, 1350, 1340 , 1300, 1270, 1250, 1230, 1200, 1175, 1105, 1090, 1060, 1040,

  1025, 990, 960, 940, 920, 895, 880, 850, 815, 795, 780, 770, 750, 720, 680, 630, 610.

NMR (CDC 1):

_ 3

  multiplet, 4H); 2 Hz, 1H); (doublet, 2.02 ppm (multiplet, 3.99 (singlet, 3H), 7.58 (singlet, 1H), J = 7Hz, 1H);

  2H); 2.37 (singlet, 3H); 3.12 7.25 (doublet of doublet, J = 7 Hz and 7, 71 (doublet, J = 2 Hz, 1 H), 8.20 (singlet, 1 H).

-16

O O

CH 30

0 OH OH

  2-acetyl-2-thoxy X-9-trihydroxy-2a, 4 to 5-tetrahydro 12,3,4-naphtha-acetone-6,1-l (i) 4-methoxy-1-deoxy-1-methoxy-2-daunomycinone Yield: 35%

P = 220-2230 ° C

  MS: m / z = 382 (15%), 346 (100%), 331 (66%), 321 (49%), 293 (30%), 247 (22%).

  IR (Paste K Br): 3250 cm (broad), 2960, 1715, 1670, 1630, 1595, 1500, 1475, 1440, 1390, 1370, 1350, 1340, 1320, 1300, 1270, 1230, 1215, 1205 1175, 1125, 1105, 1085, 1060, 1040, 1030, 1005, 985, 930, 910, 900, 870, 850, 830, 810, 785, 775, 750, 740,

730.635.

  NMR (CD C 13): 2.28 ppm (2H); 2.42 (singlet, 3H); 3.06 (singlet, 1H); 3.18 (singlet, 1H); 4.00 (singlet, 3H); 4.58 (1H); 5.30 (multiplet, L / 2 = 8.5 Hz, 1H); 7.26 (doublet of doublet, J = 7 Hz and 2 Hz, 1 H); 7, 63 (singlet, 1H); 7.70 (doublet, J = 2 Hz, 1H); 8.26 (doublet,

  J = 7 Hz, 1H); 13.43 (singlet, 1H).

17 -

CH 30 '

    2 Xj-2 Methox-9-trihydroxy-2 L (x 4 th,

  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

  cedione-6, L-7-di-4-dimethoxy-1-oxo-1-methoxy-2-daunomycinone Yield: 34% mp = 203-204 ° C

  S m / z = 382 (15%), 346 (65%), 321 (100%), 293 (58%), 268 (20%).

  IR (Pastille K Br): 3250 cm-1 (broad), 2970, 2930, 1710, 1670, 1630, 1595, 1570, 1500, 1470, 1425, 1390, 1360, 1340, 1300, 1280, 1230, 1200, 1100 1070, 1025, 985, 820. NMR (CDCl3): 2.39 ppm (singlet, 3H); 3.99 (singlet, 3H); 5.4 l (wide triplet, L 1/2 = 20 Hz); 7.25 (doublet of doublet, J = 7 Hz and 2 Hz, 1 E); 7.59 (singlet, 1H); 7.72 (doublet, J = 2 Hz, 1H); 8.25 (doublet,

  J = 7 Hz, 1H); 13.68 (singlet, 1H).

  CH 2 O -Hydroxy: 5-thoxy-3H-dihydro-1H-naphtacenetrione-2 6,11 Yield: 40%

P F = 248-250 ° C

  MS: m / z = 322 (73%), 294 (39%), 293 (24%), 280 (100%).

  IR (Pastille K Br): 2970 cm, 1710, 1660, 1620, 1590, 1570, 1490, 1455, 1450, 1430, 1415, 1375, 1340, 1290, 1260, 1230, 1190, 1150, 1075, 1020 , 1000, 915, 875, 860, 845, 820, 770, 750, 740, 680,

650.630.

  Re (CDC 13): 2.6 ppm (triplet, J = 7 Hz, 2H); 3.25 (triplet, J = 7 Hz, 2H); 3.68 (singlet, 2H); 3.98 (singlet, 3H); 7.25 (doublet of doublet,

  J = 7 Hz and 2 Hz, 11 H); 53 (singlet, 1H); 7.70 (doublet, J = 20Hz, 1H); 8.20 (doublet, J = 7 Hz, 1H); 2.93 (singlet, 1H).

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  (5) Dihydroxy-2-ethynyl-2-methoxin-8-tetrahydro-1,2,3,4-naphthacenedione-6-L-1-en-1 Yield: 43% mp = 230-2310 CS} 1 : m / z = 348 (73%), 330 (99%), 280 (100%), IP (K Br pellet): 3600 cm (broad), 3260, 2975, 2930, 1670, 1630, 1595,

  1570, 1500, 1470, 1430, 1420, 1390, 1350, 1330, 1320, 1300,

  1280, 1240, 1170, 100, 1090, 1050, 1025, 1010, 990, 970,

  930, 910, 860, 850, 840, 810, 785, 770, 755, 690.

  RM 2 (CD C 13): 2.17 ppm (triplet, J = 7 Hz, 2H); 2.49 (singlet, 1H); 3.22 (singlet, 2H), 3.08 (triplet, J = 7 Hz, 2H); 3.99 (singlet, 3H); 7.27 (doublet of doublet, J = 7 Hz and 2 Hz, 1H); 7.54 (singlet, 1H); 7, 72 (doublet, J = 2 Hz, 1H); 8.22 (doublet, J = 7 Hz, 1H); 2.97 (singlet, 1H).

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_ 20 -

  CH 2 (-) -2-Acetyl-2,5-dihydroxy-8-tetrahydro-1,2,3,4-tetrahydro-6α-tetrahydione (4-methoxy-7-dideoxy-3-methoxy-daunomnycinone Yield: 98%

P F = 208-210 ° C

  M: m / z = 366 (8%), 343 (4%), 323 (100%), 305 (25%), 293 (16%), 280 (12%), I.R (Pastille)

  K Br): 3500 cm, 3060, 2960, 1700, 1660, 1630, 1590, 1560, 1540, 1480, 1420, 1380, 1350, 1340, 1330, 1290, 1275, 1240, 1200, 160, 1105, 1080, 1030, 1000, 990, 980, 950, 925, 910, 895, 860, 850, 825, 810, 800, 770, 750, 720, 710, 630.

  R 1 'U (CD C 13): 2.02 ppm (triplet, 2H); 2.37 (singlet, 3H); 3.07 (multiplet, 4H) 3.99 (singlet, 3H); 7.26 (doublet of doublet, J = 7 Hz and 2 Hz, 1 H); 7.54 (singlet, 1H); 7.72 (doublet, J = 2 Hz, 1H); 8.23 (doublet, J = 7Hz, 1H); 12.99 (singlet, 1H) _ 2 I

O O

CH 30

H OH

  () 2-Acetyl-2-methoxy-3-hydroxy-4-tetrahydro-1 2 3 4-naphtacenedione-611 () 4-methoxy-3-methoxy-3-methoxy-daunomycinone Yield: 36%

P = 222-2230 ° C

  MS: m / z = 382 (15%), 346 (100%), 331 (66%), 321 (49%), 293 (30%), 247 (22%).

  IR (K Br pellet): 3540 cm -1, 2980, 2970, 1700, 1660, 1630, 1590, 1570, 1450, 1420, 1380, 1350, 1330, 1310, 1300, 1280, 1250, 1240, 1200, 1160, 1120, 1105, 1100, 1080, 1020, 1010, 990, 970, 930, 900, 880, 840, 820; 800, 770, 760, 630. Pan I (CD C 13): 2.28 ppm (multiplet, 2H); 2.4 l (singlet, 3H); 4.00 (singlet, 3H); 5.23 (multiplet, L 1/2 = 10 Hz, 1H); 7.25 (doublet of doublet,

  J = 7H) and 2 Hz, 1H); 7.61 (singlet, 1H); 7.70 (doublet, J = 2HZ 1H) 8.26 (doublet, J = 7Hz, 1H); 13.19 (singlet, 1H).

_ 22 _ 2-5 51 0 5 7

(+) Acety H 2 m -OH

CH 3 O

  () Acet-2-methoxy-8-trihydroxynyl 4-pentahyd E 2 zl, 2, z 4 h

dione-6 I 1 l.

  (Epi-7 demethox xy-11 methoxy-3 daun mycinope Yield: 42.5%

* MS: m / z = 382 (11%), 346 (100%), 321 (97%), 293 (50%), 268 (16%), 247 (21%).

  -1 I.R (Paste K Br) 3490 cm (broad), 2960, 2930, 1720, 1670, 1640, 1600,

  14301390, 1360, 1340, 1290, 240, 1170, 1105, 1095, 1040, 1020, 910.

  NMR (CD C 13): 2.40 ppm (singlet, 3H); 4.30 (singlet, 3H); 5.43 (broad triplet, L 1/2 = 20 Hz, 1H); 7.25 (doublet of doublet, J = 2 Hz and 7 Hz, 1 H);

  7.60 (singlet, 1H); 7.73 (doublet, J = 2 Hz, 1H); 8.25 (doublet, J = 7 Hz, 1H) 13.45 (singlet, 1H).

O OH O

OH O

  () 4-Demethoxy-4-dideoxy-4-hydroxy-daunomycinone () 2-acetyl-triethylrox-Z 22 t bxttraydro-1234 na Ehtacenedione-6,11 Yield: 97% Mp = 1 S: M: m / z = 352 ( 6%), 334 (20%), 309 (100%), 291 (24%), 280 (20%), 279 (23%), 266 -1 (32%) IR (Paste K Br): 3505 cm, 2940, 2860, 1700, 1630, 1590, 1490, 1460,

  1430, 1400, 1340, 1290, 1230, 1190, 1170, 120, 1090, 1060, 1050, 965, 930, 915, 835, 815, 790, 730, 700.

  NMR (CDCl3): 2.39 (singlet, 3H); 3.08 (multiplet, 4H); 7.2-7.8 (multiplet, 36H); 12.70 (singlet, 1H); 13.09 (singlet, 1H).

23 -

O OH

OH O

  1) (Ethyllnedioyl-1: 1H-Yl) -2-dtridro-2-tetrahydrog-12 3,4 Laphtacenedione T-611 Yield: 98% Mp: 216-217 MSC: m / z = 396 (0.5%) ), 308 (85%), 266 (100%)

  IR (K Br pellet): 3440 cm, 3000, 2950, 1640, 1600, 1570, 1480, 1460, 1430, 1400, 1380, 1360, 1320, 1310, 1280, 1260, 1200, 1170, 1100, 1,090, 1080, 1060, 1040, 970, 955, 930, 910, 890, 850, 840, 800, 780, 730, 700, 650.

  NMR (CDCl3): 1.43 ppm (singlet, 3H); 2.0 (multiplet, 2H); 2.94 (multiplet, 4H); 4.08 (singlet, 4H); 7.5 (multiplet, 4H); 12.73 (singlet, 1H);

13.08 (singlet, 1H).

O OH O

(J OH

H O OH

  2-acetyl-etrahd 4 x 712 ttradro-123, nahtacedione (t) 4-Demethoxy-6-deoxy-4-hydroxy-1-enone or 6-deoxycarminomycinon Yield: 28%

M.p. 219-221 ° C.

  MS: m / z = 368 (8%), 350 (19%), 332 (32%), 307 (78%), 279 (100%). 30? 1R (Paste K Br): 3530 cm 3 060, 2960, 2930, 1710, 1630, 1600, 1570, 1470, 1450, 1420, 1390, 1250, 1220, 1180, 1170, 1130, 1080, 1055, 1030, 950, 910, 900, 840, 790. NMR (CDCl3): 2.3 ppm (multiplet, 2H); 2.42 (singlet, 3H); 3.07 (singlet, 2H); 4.95 (multiplet, L 1/2 = 8.6 Hz, 1H); 7.25-8.04 (multiplet, 4H11);

  12.71 (singlet, 1H); 13.14 (1H).

255 1 O 5 7

_ 24 -

  o) 1-Dihydroxy-2,5-tetrahydro-1 2 3 4 naphthalenedione-6 11

  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ X _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _

  DPEM Eithoxy-4-desacetyl-9-deoxy 71 1 daunomine. 10 Yield: 98%

M.p. 283-2850 ° C .;

  MS: m / z = 294, 276 I 1 R (K Br pellet): 3400 cm (broad), 2960, 1660, 1630, 1590, 1570, 1470, 1410, 1380, 1360, 1330, 1320, 1270, 1250, 1200, 111160, 1090,

  1060, 1050, 1000, 970, 920, 820, 800, 710.

  () Acetox Z 2 -hydroxy-tetrahydro-12,3 4-naphthacenedione 6111 (4-acetyl-9-demethoxy-4-desacetyl-9-deoxy-1-one dalomcinone Yield: 80%

Mp 205-206 ° C

  MS: m / z = 336 (7%); 276 (100%).

  IR (K Br pellet): 3440 cm (broad), 2975, 1730, 1670, 1625, 1590, 1570, 1480, 1430, 1410, 1380, 1370, 1350, 1290, 1280, 1250, 220, 1060, 1040, 970, 930, 790, 750, 725. RIMN (CD C 13): 2.0 ppm (multiplet, 2H); 2.07 (singlet, 3H); 2.9

  (multiplet, 4H, 5.23 (broad triplet, L1 / 2 = 13Hz, 1H), 7.4 (singlet, 1H), 7.7 (multiplet, 2H), 8.15 (multiplet , 2H), 12.8 (singlet, 1H).

  2-Acetoxy-2-adrenoethoxy-4-tetrahydro-2-ylacetone-6 L () O-acty 1 1-9 4-demethoxy-9-deacetyl-deoxy-11-daunomycinone Yield: 28 %

P = 182-183 ° C

  MS: m / z = 352 (1.5%), 292 (60%), 274 (100%).

  I.R (Paste K Br): 3500 cm, 2980, 2960, 1730, 1670, 1630, 1590, 1520,

  1480.1 1430, 1420, 1390, 1370, 290, 1270, 1250, 1060, 1030, 970, 800, 790, 720.

  NMR (CDCl3): 2.07 ppm (singlet, 3H); 2.33 (multiplet, 2H); 3.1 (doublet, J = 4 Hz, 2H); 3.67 (doublet, J = 4 Hz, 1H); 5.23 (multiplet, L / 2 = 16 Hz, 2H); 7.5 (singlet, 1H); 7.8 (multiplet, 2H); 8.23 (multiplet, 2H);

13.2 (singlet, 1H).

5 1 0 5 7

_ 26

Q OAC

O OH OH

  () 2-Acetoxy-4,5-dihydroxytetrahydro-1 L 2 3 L 4 -naphtacenedione-6 11 1 -Eu 2 -p-acetyl-9-methoxy-4-desacetyl-deoxy ldaunomycinone Yield: 49% mp = 222-227 ° C (Dec)

  MS: m / z = 352 (1%), 292 (18%), 274 (100%).

  I.R (Paste K Br): 2980, 2960, 1720, 1670, 1630, 1590, 1570, 1480, 1450, 1420, 1390, 365, 1355, 1330; 1290, 1280, 1250, 1240, 1100, 1070, 1060, 1040, 980, 950910, 830, 790, 730.

  NMR (CD C 13): 2.07 ppm (singlet, 3H); 5.36 (multiplet, L 1/2 = 11.5 Hz, 2H); 7.59 (singlet, 1H); 7.80 (multiplet, 2H); 8.25 (multiplet, 2H);

13.37 (singlet, 111).

HO O

CCH

  2-OH-thynyl-5-trihydroxy-5,10-tetrahydro-1,212-tetrahydroxy-6111-hexanoate Yield: 60%

Mp 225-226 ° C

  1 R (CH 2 Cl 2): 3420 cm, 3300, 2960, 2940, 1640, 1610, 1580, 1485, 1475,

  1460, 1430, 1395, 1340, 1320, 1270, 1205, 1195, 1165, 1150, 1095,

  1060, 1050, 1030, 1000, 960, 915, 840, 780.

  MS: m / z = 334 (12%), 333 (54%), 316 (45%), 307 (55%), 280 (39%), 266 (100%).

2551 057

_ 27 _

HO O

  (+) Acetyl-2-trihydroxy-2-yl 5,3-tetrahydro-12,3-tetrahydro-12,4-tetrahydione-6 11 __ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Quantitative yield 10

Mp = 226-228 ° C

  N: m / z = 352 (26%), 309 (100%), 291 (42%), 279 (37%), 266 (18%) 9,205 (24%),

  189 (24%), 164 (22%), 152 (25%), 121 (53%), 115 (41%), 93 (46%), 91 (46%).

I.R (K Br)

20 25

  : 3460 cm, 2920, 1860, 1705, 1635, 1625, 1615, 1610, 1600,

  1580, 1570, 1470, 1450, 1400, 1395, 1365, 1335, 1280, 1270, 1190, 1160, 1105, 1090, 1050, 970, 950, 905, 800, 785, 710.

HO O

O OH OH

0 OH OH

  (2-Acetyl-2-ttrahydroxy: L 2 oc-4 X-5 lo ttrahdro 1 2 z 3 L 4 _Unhtac nedione-6,11 F = 209-211 lC I.R (K Br) -l

  3500 cm, 3350, 2940, 1695, 1610, 1580, 1475, 1455, 1420, 1395, 1175, 1340; 1320, 1275, 1245, 1210, 1160, 1120, 1090, 80, 1060, 1030, 975, 940, 905, 900, 840, 810, 800, 730, 695.

  ## EQU1 ## ## where ## EQU1 ## where ## EQU1 ## 06 'O 9 I' ç 9 g OZLI '099 Z' & Oú 6 Z & o 6 the OZ E 'I mz 08 where: (lx I) to (% OI) O OI' (Z 69) 90 the (Z Zg) 6 ll '(% E) Iú 1' (Zo 0) ço '' (Z 8 l) 61 Z '(% 6 Z) Lo O' (Zlr) LlE '(Zl) Zúú' (Z 11) 89 ú z / M: R'S Do 91 Z-60 Z: O HO o

O O OH

8 Z-

L 50 LSSZ

Claims (16)

  New aglycones useful for the preparation of antibiotics and antitumour agents characterized in that they correspond to the following general formula IV: R 1 Q, R 7 R 2 (IV) R 3 R 5 O R 6 OH   in which: R 1, R 2, R 3 and R 5, which may be identical or different, represent a hydrogen atom or an OH, OMetal or OR 4 group,   R 4 is a substituted or unsubstituted C 1 -C 6 alkyl group.   R represents a hydrogen atom or an OCH 2 group R ', R' being   Hydrogen, alkyl, hydroyl, alkoxyl or aryl.   R 6 and R 7, which are always different, represent either an atom hydrogen is an OH group.   R represents a hydrogen atom or the group CH 3 OOsus reserves that: 1) * R 1, R 2 and R 3 are never hydrogen at a time when R 7 and R 8 represent the atom of hydrogen and the R is the group COCH 2 R '.   2) If R 1, R 2, R 3 and R 6 are hydrogen, R 5   is different from hydrogen and OCH 3.   2 Aglycones according to claim 1, characterized in that the two OH groups of the ring A are in the cis position relative to each other.   3 Aglycones according to claim 1, characterized in that the two OH groups of the A ring are in the trans position. relative to each other.   4 aglycones according to any one of the claims   1 to 3, characterized in that they are deoxy-11 aglycones. i: 10 5 7     Aglycones according to any one of the claims   1 to 3, characterized in that they are 6-deoxy aglycones. Aglycones according to Claim 4, characterized in that they are taken from the group which comprises the aglycone in which R 1 = CH; R 2 = R 3 = R 5 = H; R 6 = OH; R = COCH 3; R 8 = H the aglycone in which R 1 = R 3 = R 5 = H; R 2 = COCH 3; R 6 = CH; R = COCH 3; R 8 = H the aglycone in which R 1 = R 2 = R = H; R 3 = OCH 3, R 6 = OH; R = CCH 3; R 8 = H the aglycone in which R 1 = R 2 = R 3 = R 5 = R = H; R 6 = CH; R 8 = COCH 3 10 7 Aglycones according to claim 5, characterized in that they correspond to the product in which: R 1 = R 2 = R 3 = R 6 = H; R 7 = OH; R 5 = OH; R = COCH 3 8 Process for the preparation of the deoxy-11 aglycones according to the present invention, which process is characterized by the following steps: 1st stage: Pr Eéaration of the enol ether of general formula VR 1 O- Alkyl Re R 3 R 5 O H   R 1, R 2, R 3 and R 5 having the same meaning as above by the action of a halogenated naphthoquinone of general formula VI on   a diene of general formula VII. R 1 O   R 30 R 3 + Alkyl O-Alkyl 3: O Alkyl-O Alkyl O-Si / Alkyl (VI) (VII) Alkyl   R 1, R 2, R 3 and R 5 having the same meaning as above and X represents a halogen atom.   31 - Step 2: Hydrolysis of enol-V ether in ketone   corresponding of general formula VIII. R 1 O O (VIII)   3rd summer 15 ape: Ethynylation of ketone VIII as a product of corresponding formula IX. Ri 1 R C CH "H (IX) R 5 O OH   followed by hydration in the product of general formula X R 1 O O   R 2 (x) R 3 O 4 th step: Benzyl bromination followed by basic hydrolysis leading to the desired product. Process for the preparation of the 6-deoxy aglycones according to the present invention, which method is characterized in that during the first step   a diene of general formula XI is used.   Alkyl O Alkyl Alkyl Si_ OO Alkyl / (XI)   the other steps being similar to the process described for the deoxy-11 derivatives of claim 8. 2551057 32     Compound of which one of the antipodes is represented by the general formula XII R C-CH OH (XII) O OH   in which R 1, R 2, R 3 have the same meaning as above, an aglycone synthesis intermediate according to claim 1. A compound of which one of the antipodes is represented by the general formula XIII R 1 O O 11 - R 2 R 3 (XIII)   In which R 1, R 2 and R 3 have the same meaning as above, intermediate of synthesis of aglycones according to claim 1.   12 Compound of which one of the antipodes is represented by the formula XIV O OH O   o (X IV) aglycone synthesis intermediate according to the claim 1.   13 A compound of which one of the antipodes is represented by the formula XV 0 OH 61 b H (XV) intermediate for the synthesis of aglycones according to claim 1.   33 - 14 Compound of which one of the antipodes is represented by the formula XVI O OH x OH (XVI) HO O OH   Aglycone synthesis intermediate according to claim 1.     Compound of which one of the antipodes is represented by the formula XVIII (XVIII) O OH   aglycone synthesis intermediate according to the claim 1.   16 'A compound of which one of the antipodes is represented by the formula XVII OAC (XVII)   aglycone synthesis intermediate according to the claim 1.   17 A compound of which one of the antipodes is represented by the formula XIX O A / A ,, O Ac (XIX) OH   aglycone synthesis intermediate according to claim 1.